OVERALL PROJECT SUMMARY Leukemias affect about 60,000 individuals, and cause the death of 24,000 individuals annually in the US. The Leukemia SPORE renewal application builds upon progress achieved in the previous funding periods, which contributed to several changes in the standards of care in leukemia. It proposes five important novel mechanistic strategies which if successful, will establish new standards of therapies in leukemia: epigenetic therapy modulation; immunotherapy with a new monoclonal antibody Hu-8F4; non-genotoxic p53 modulation by MDM2 inhibition; novel natural-killer (NK) cellular therapy; targeting oxidative phosphorylation ( OxPhos) in leukemia with novel OxPhos inhibitors. Our overall goal is to discover/enhance these new therapies through a better understanding of the causal pathophysiologies in leukemia and the identification of actionable targets. We propose five fully translational research projects (laboratory to clinic and back) supported by three cores. The overall Specific Aims are: 1) Optimize and improve the efficacy of epigenetic therapies in AML (Project 1). This research area was developed by Project 1 co-leaders over the past 14 years, and resulted in the FDA approval of decitabine as an epigenetic therapy for MDS, and the European EMEA approval (2012) for the treatment of elderly AML unfit for intensive chemotherapy. The new aims investigate enhancing the epigenetic effects through suppression of CDK9. 2) Explore anti-leukemic effects of a novel targeted immune therapy using 8F4 monoclonal antibody (Project 2). Previous work through this SPORE resulted in the development of the PR1 vaccine and the discovery of a newly discovered humanized T cell receptor-like antibody (8F4) with specificity for a conformational epitope of PR1 in vitro and in vivo. . Project investigators will now test the efficacy of the new 8F4 antibody and conduct a phase I clinical trial to determine its anti- AML efficacy, and understand the mechanisms behind its success/failure in patients treated. 3) Explore strategies to enhance non-genotoxic p53 activation by MDM2 inhibition in AML (Project 3). Previous work introduced p53-targeted therapy in leukemia as promising. Investigators will now extend these findings using preclinical and clinical studies of novel MDM2 inhibitors and combinations with apoptosis inducing agents (venetoclax). 4) Investigate NK-CAR cellular therapy in leukemia (Project 4). This is an in-house therapeutic strategy funded through a Leukemia SPORE CEP and showing promising translational therapeutic value. 5) Develop OxPhos- based targeted therapies in leukemia (Project 5). This is another in-house developed approach and molecule investigated by investigators previously supported by a Leukemia SPORE DRP, and expanded into a full project based on its promising results.